Take your vitamins...and die?

This meta-analysis was published online only yesterday, and it is already going all around the net and the press. Why? Because the authors of the analysis found that

Vitamin A, beta-carotene, and vitamin E may increase mortality.

Moreover, the results for vitamin C were inconclusive. Does it mean that taking vitamins is not only useless, but can even increase your chance to die? I cannot seem to access the full text of this review. However, I thought it would be interesting to go over the methods, the main findings, and the authors' recommendations.

But first of all, some of us out there might be wondering....what is the Cochrane Collaboration? Is this organization reliable or does it call for a hefty dose of skepticism a priori?

More below the fold.

What is the Cochrane Collaboration

The Cochrane Collaboration is a non-for-profit organization founded in 1993. It has little staff, and it is run mainly by a huge number of volunteers, most of whom are medical professionals and/or researchers at universities around the world, and whose main effort is the production of the Cochrane Reviews. The main aim of the Reviews is to try and make sense out of thousand of studies, mainly clinical studies and trials, and to come out with a "state of the union" report which can give medical professional and consumers an idea about what the evidence is, at the moment, pro or contra the use of certain medicines and/or treatments. The video gives you a short introduction to the Cochrane Collaboration.



In case you still have no idea about who these people are...I am sure you have heard of them before. Do you remember the not-so-groundbreaking news that vitamin C really does not help with curing or preventing colds? Well, that was also a result from one of their meta-analyses.

Can we trust data coming out from the Cochrane Reviews? I would suggest that the problem is not with the effort itself, but more with the fact that meta-analyses always come with huge caveats: the data were not collected coherently, probably different parameters were measured in different studies, most probably different statistical methods were used, and it is also quite hard to identify all possible confounding variables. When you look at people affected by a disease, and decide that the vitamins were increasing their risk of death...are you sure that disease progression was not the main confounding variable behind that figure?

Let's find out.

Aim of the study and data collection

The main aim of the study, as stated by the reviewers, was

To assess the effect of antioxidant supplements on mortality in primary or secondary prevention randomised clinical trials.

The authors then searched for studies using their own database, MEDLINE, EMBASE,
the Science Citation Index Expanded, and even wrote to pharmaceutical companies for additional information. I do not know how significant this "additional information" was, but it is interesting that they decided to do this, as I wonder how they then assessed the quality of such information.

All studies reporting on the results of primary and secondary prevention randomized clinical trials on beta-carotene, vitamin A, vitamin C, vitamin E, and selenium (versus placebo or no intervention) were included in the review. Participants in these studies were either healthy (primary prevention trials) or not (secondary prevention trials). The authors then tried to assess "bias" for each study, analyzing each of the studies considered for blinding, randomization and follow-up:

Trials with adequate randomisation, blinding, and follow-up were classified as having a low risk of bias. Random-effects and fixed-effect meta-analyses were performed. Random-effects meta-regression analyses were performed to assess sources of intertrial heterogeneity.

Main findings

Here is the quotation, from the review's abstract, describing the results (emphasis and links mine):

Sixty-seven randomised trials with 232,550 participants were included. Forty-seven trials including 180,938 participants had low risk of bias. Twenty-one trials included 164,439 healthy participants. Forty-six trials included 68111 participants with various diseases (gastrointestinal, cardiovascular, neurological, ocular, dermatological, rheumatoid, renal, endocrinological, or unspecified). Overall, the antioxidant supplements had no significant effect on mortality in a random-effects meta-analysis (relative risk [RR] 1.02, 95% confidence interval [CI] 0.99 to 1.06), but significantly increased mortality in a fixed-effect model (RR 1.04, 95% CI 1.02 to 1.06). In meta-regression analysis, the risk of bias and type of antioxidant supplement were the only significant predictors of intertrial heterogeneity. In the trials with a low risk of bias, the antioxidant supplements significantly increased mortality (RR 1.05, 95% CI 1.02 to 1.08). When the different antioxidants were assessed separately, analyses including trials with a low risk of bias and excluding selenium trials found significantly increased mortality by vitamin A (RR 1.16, 95% CI 1.10 to 1.24), beta-carotene (RR 1.07, 95% CI 1.02 to 1.11), and vitamin E (RR 1.04, 95% CI 1.01 to 1.07), but no significant detrimental effect of vitamin C (RR 1.06, 95% CI 0.94 to 1.20). Low-bias risk trials on selenium found no significant effect on mortality (RR 0.91, 95% CI 0.76 to 1.09).

Although I did not have the privilege to look at the full study, this does mean that bias inherent to each study was considered, and that a statistical model controlling for certain time-fixed heterogeneity (think ethnicity, location, and so on) was used. Their results all seemed to be within the 95% confidence interval.

So, what does it mean?

Again, in the words of the authors:

We found no evidence to support antioxidant supplements for primary or secondary prevention. Vitamin A, beta-carotene, and vitamin E may increase mortality. Future randomised trials could evaluate the potential effects of vitamin C and selenium for primary and secondary prevention. Such trials should be closely monitored for potential harmful effects. Antioxidant supplements need to be considered medicinal products and should undergo sufficient evaluation before marketing.

The results suggest that certain vitamins studied, and known to be antioxidants, have no effect used in a preventative manner on healthy or unhealthy patients, and actually all of them, with the exclusion of vitamin C and selenium, seemed to increase mortality. It must also be said that the authors did not consider cases when individuals were given vitamins because they were vitamin-deprived (that would have confounded the results).

Also, the results were obtained in the fixed-effect analysis, but not in the random-effect analysis. What does it mean? First of all, we need to understand what the difference between the two models is:

A fixed effects ANOVA refers to assumptions about the independent variable and the error distribution for the variable. An experimental design is the easiest example for illustrating the principal. Usually, the researcher is interested in only generalizing the results to experimental values used in the study. For instance, a drug study using 0 mg, 5 mg, or 10 mg of an experimental drug. This is when a fixed effects ANOVA would be appropriate. In this case, the extrapolation is to other studies or treatments that might use the same values of the drug (i.e., 0 mg, 5 mg, and 10 mg). However, if the researcher wants to make inferences beyond the particular values of the independent variable used in the study, a random effects model is used. A common example would be the use of public art works representing low, moderate, and high abstractness (e.g., statue of a war hero vs. a pivoting geometric design). The researcher would like to make inferences beyond the three pieces used, so the art pieces are conceptualized as pieces randomly drawn from a larger universe of possible pieces and the inferences are made to a larger universe of art work and range of abstractness values. Such a generalization is more of an inferential leap, and, consequently, the random effects model is less powerful.

It would be nice to see how, in this review, they actually analyzed the data, because I cannot really see that from the abstract. Did the studies they decided to look at use similar, if not the same, methods of administration of supplements? It does seem, from their summary, that only a certain range of values was considered.

Do the results mean that you should stop taking your vitamins otherwise you'll die? As the authors themselves say, these results grant the need for further investigation into harmful effects of certain supplements. This does not necessarily mean you will die because of vitamins - as correlation with higher mortality does not necessarily imply causation. But it does at least suggest that using vitamins is useless, unless you really need them - in which case, you are usually severely food-deprived.

Update: Holford Watch also weighs in, but focuses on some of the responses to the study. Skeptical responses...but not coming out of genuine skepticism. Check it out!

Citation

Bjelakovic, G., Nikolova, D., Gluud, L.L., Simonetti, R.G. (2008). Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases.. Cochrane Database of Systematic Reviews, ?(2), ?-?.

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